MHC-class I restricted peptide-based immunomodulation of CD8+ T and NK cells

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MHC-CLASS I RESTRICTED PEPTIDE BASED IMMUNOMODULATION OF CD8

T AND NK CELLS

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ABSTRACT

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TABLE OF CONTENTS

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1.3 NATURAL KILLER (NK) CELLS

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1.3.1 NK cell development

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'+C(% D((,% #D8("C(/^iTLiMF% I*#,% :(+C0,5% &'(% D#,(% $+""#=% O9% 1(::8% 1+,% "(80/(% 0,% &'(%

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"(8*#,/% +5+0,8&% *+&'#5(,8F% >8% -#"% U% 1(::82% O9% 1(::8% 1#,&0,4(% &#% $+&4"+&(% 0,% &'(%

*("0*'("?%-#::#=0,5%(K0&%-"#$%&'(%&'?$48%+,/%&'(%D#,(%$+""#=2%"(8*(1&0C(:?^iPLMBF%

% P%

1.3.2 NK cell triggering

<0$0:+":?% &#% U% 1(::82% -4,1&0#,+:% +1&0C+&0#,% #-% O9% 1(::8% "(f40"(8% +% ,4$D("% #-% +1&0C+&0,5%

8&0$4:0% -#"% (--010(,&% (--(1&#"% -4,1&0#,8F% E,5+5($(,&% #-% +% 80,5:(% #"% 8(C("+:% +1&0C+&0,5%

"(1(*&#"8% W<05,+:% BX% 1+,% *"#$#&(% O9% 1(::% +1&0C+&0#,% +,/% 1:#,+:% *"#:0-("+&0#,F% V,% &'(%

#&'("% '+,/% 6)@Q2% ='01'% *:+?8% +,% (88(,&0+:% "#:(% 0,% U% 1(::% 1#L8&0$4:+&0#,% W<05,+:% @X2% 08%

(K*"(88(/%+&%:#=("%:(C(:8%0,%O9%1(::8%1#$*+"(/%&#%,+0C(%U%1(::8F%G'0:(%8&0$4:+&0#,%#-%

6)@Q% 0,% O9% 1(::8% 08% ,#&% "(f40"(/% -#"% 1?&#&#K010&?2% 0&% 8(($8% &#% D(% 1(,&"+:% -#"% #*&0$+:%

1?&#;0,(% 8(1"(&0#,% +,/% *"#:0-("+&0#,^M@F% V&'("% 80$0:+"0&0(8% D(&=((,% &'(% &"055("0,5% #-% U%

+,/% O9% 1(::8% 1#$*"08(% &'(% 48(% #-% *"#L0,-:+$$+&#"?% 1?&#;0,(8% 7bLB@% +,/% &?*(L7% 7!O8%

*"#C0/(/%D?%)68%4*#,%8(,80,5%C0"+:%0,-(1&0#,%W<05,+:%TX^MTLMiF%7&%8'#4:/%+:8#%D(%,#&(/%&'+&%

(C(,% 0,% &'(% +D8(,1(% #-% 805,+:8% B% +,/% @2% 805,+:% T% +:#,(% 1#4:/% *"#$#&(% +,% 0,,+&(L:0;(%

+D0:0&?%0,%$($#"?%6Ub8%&#%*"#/41(%7!O!%+,/%*"#:0-("+&(^MM2MQF%%

7,% 1#,1:480#,2% &'(% $(1'+,08$8% #-% 0,&(5"+&0,5% +1&0C+&0#,2% 1#L8&0$4:+&0#,% +,/% 1?&#;0,(%

805,+:0,5%8(($%&#%D(%1#$$#,%&#%D#&'%O9%+,/%U%1(::8F%%%

1.4 ROLE OF MHC IN DEVELOPMENT AND REGULATION OF T AND NK CELLS

.36%08%+%;(?%$#:(14:(%0,%8(C("+:%/0--("(,&%8&+5(8%#-%U%1(::%D0#:#5?F%U'(%0$*#"&+,1(%#-%

.36%0,%&'?$01%(/41+&0#,2%*("0*'("+:%&#:("+,1(2%U%1(::%+1&0C+&0#,%+,/%(--(1&#"%-4,1&0#,8%

"(84:&8% 0,% +% D0+8% #-% &'(% U6a% &#=+"/8% .36F% O#,L8(:-% +,/% 8(:-L*(*&0/(% +,&05(,8% +"(%

1#,&0,4#48:?%/08*:+?(/%#,%.36%&#%!" U%1(::8%+1&0,5%+8%+%=0,/#=%&'+&%(K'0D0&8%&'(%0,,("%

8&+&48%#-%&'(%1(::F%7,%#&'("%=#"/82%.36%$#:(14:(8%-#"$%+%*:+&-#"$%-#"%&'(%/#1;0,5%+,/%

81+,,0,5% #-% C+"0#48% /0--("(,&% U6a8% /4"0,5% &'(0"% f4(8&% &#% /081#C("% 1#5,+&(% *(*&0/(%

+,&05(,8%+,/%0,%#"/("%&#%;((*%U%1(::LD+8(/%+/+*&0C(%0$$4,(%"(8*#,8(8%+:("&%+,/%+1&0C(F%

>:&'#45'%&'(0"%5(,(%:#10%+"(%:#1+:0[(/%#,%/0--("(,&%1'"#$#8#$(82%U6a%+,/%.36%'+C(%

1#L(C#:C(/%80,1(%&'(%1"(+&0#,%#-%+/+*&0C(%0$$4,(%8?8&($8%0,%C("&(D"+&(8F%7&%'+8%D((,%

"(1(,&:?%'?*#&'(80[(/%+,/%*+"&0+::?%*"#C(,%&'+&%U6a8%$+;(%48(%#-%5("$:0,(%(,1#/(/%

(C#:4&0#,+"0:?% 1#,8("C(/% "(80/4(8% :#1+:0[(/% #,% &'(% 1#$*:($(,&+"0&?% /(&("$0,0,5%

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($("5(,1(%#-%"(1(,&%1'+::(,50,5%-0,/0,58^QBFQ@2QT2%0&%08%5(,("+::?%1#,80/("(/%&'+&%!" U6a8%

1+,,#&% "(1#5,0[(% +,&05(,8% &'+&% +"(% ,#&% *"(8(,&(/% D?% .36F% U'08% 08% #,(% #-% &'(% $+]#"%

0,/01+&0#,8%-#"%&'(%(88(,&0+:%"#:(%#-%.36%$#:(14:(8%0,%U%1(::%"(1#5,0&0#,F%!4"&'("$#"(2%

U%1(::8%&'+&%+"(%#,:?%"(+1&0C(%&#%8(:-L*.36%$#:(14:(8%+"(%+::#=(/%&#%$+&4"+&(%/4"0,5%

&'?$01%(/41+&0#,F%U%1(::8%(/41+&(/%0,%&'(%+D8(,1(%#-%8(:-L*.36%1+,%8&0::%"(1#5,0[(%.36%

$#:(14:(82%+:&'#45'%$#8&%-"(f4(,&:?%+::#5(,(01^QRF%%

!0,+::?2%*"(8(,1(%#-%.368%+,/%&'(0"%+D0:0&?%&#%*"(8(,&%+,&05(,01%*(*&0/(8%08%#,(%#-%&'(%

"(f40"($(,&8%&#%0,0&0+&(%&'(%805,+:8%&'+&%+"(%,(1(88+"?%&#%&"055("%U%1(::8F%!#"%(K+$*:(2%

-#"$+&0#,%#-%&'(%0$$4,#:#501+:%8?,+*8(%/4"0,5%UL1(::%+,/%>H6%0,&("+1&0#,8%08%$(/0+&(/%

&'"#45'% .36% +,/% U6aF% U'482% 0,% #"/("% &#% +1f40"(% +% D(&&("% 4,/("8&+,/0,5% #-% &'(%

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BA%%

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&'(%D0#:#5?%#-%D#&'%.36%+,/%U6aF%

<0$0:+":?% &#% U% 1(::8% &'+&% 4,/("5#% *#80&0C(% +,/% ,(5+&0C(% 8(:(1&0#,% 0,% &'(% &'?$482%

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='("(+8%-+0:4"(%&#%(,5+5(%0,'0D0&#"?%"(1(*&#"8%/4"0,5%/(C(:#*$(,&%"(84:&8%0,%O9%1(::%

'?*#L"(8*#,80C(,(88^QiLPAF% I,:0;(% Y/(+&'% D?% ,(5:(1&Z% 8((,% 0,% U% 1(::% 8(:(1&0#,2% O9% 1(::8%

&'+&%/#%,#&%5(&%8&0$4:+&(/%D?%0,'0D0&#"?%:05+,/8%/4"0,5%/(C(:#*$(,&%+"(%8&0::%(K*#"&(/%

&#% &'(% *("0*'("?% D4&% "($+0,% +,("501F% U'08% *"#1(88% ='("(% (--(1&#"% -4,1&0#,8% +"(%

1#,-(""(/%4*#,%&'#8(%O9%1(::8%&'+&%'+C(%&'(%+D0:0&?%&#%8(,8(%&'(%*"(8(,1(%#-%.36L7%08%

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(K+$*:(%#-%841'%+%*'(,#$(,#,%08%&'(%+1f4080&0#,%#-%(--(1&#"%-4,1&0#,8%D?%*"(C0#48:?%

+,("501% O9% 1(::8% &"+,8-(""(/% 0,&#% +,% .36L7% 84--010(,&% (,C0"#,$(,&2% 8455(8&0,5% &'+&%

1#,&0,4#48% (,5+5($(,&% #-% 0,'0D0&#"?% "(1(*&#"8% =0&'% .36L7% 08% "(f40"(/% -#"% O9% 1(::%

"(8*#,80C(,(88F%O#&+D:?2%O9%1(::8%&'+&%:+1;%+,%0,'0D0&#"?%"(1(*&#"%-#"%+4&#:#5#48%.36L7%

1+,% 8&0::% "(8*#,/% ,#"$+::?% 0,% 0,-:+$$+&#"?% 8(&&0,58^QQ2PR2PS% +,/% $#"(% "#D48&:?% +5+0,8&%

C0"+:% 0,-(1&0#,8% +,/% :(4;($0+% &'+,% &'(0"% 1#4,&("*+"&8% &'+&% (K*"(88% 8(:-L8*(10-01%

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>//0&0#,+::?2%:05+&0#,%#-%/(C(:#*0,5%O9%1(::8`%+1&0C+&0,5%"(1(*&#"8%=0&'%1#5,+&(%C0"+:%#"%

8(:-L:05+,/8% :(+/8% &#% +,("5?% +8% =(::% +8% +% *+"&0+:% "(*("&#0"(% /(:(&0#,% "(8($D:0,5% &'(%

,(5+&0C(%8(:(1&0#,%#-%/(C(:#*0,5%&'?$#1?&(8^PPLBA@F%%

1.5 THREE-DIMENSIONAL STRUCTURE OF MHC MOLECULES

.36% $#:(14:(8% +"(% $+0,:?% "(*"(8(,&(/% D?% &=#% /08&0,1&% 1:+88(82% 7% +,/% 772% 0,% '05'("%

C("&(D"+&(8F% .36L7% $#:(14:(82% ='01'% -#"$% &'(% $+0,% "(1#5,0&0#,% *:+&-#"$% -#"% 6Ub82%

*"(8(,&% #,% &'(% 1(::% 84"-+1(% (,/#5(,#48% +,&05(,8% &'+&% "(84:&% -"#$% &'(% *"#1(880,5% #-%

1?&#8#:01%*"#&(0,8F%7,%1#,&"+8&%&#%.36L7%&'+&%+"(%(K*"(88(/%D?%+::%,41:(+&(/%1(::82%.36L 77% +"(% #,:?% (K*"(88(/% D?% *"#-(880#,+:% >H68% 841'% +8% )682% $+1"#*'+5(8% +,/% J% 1(::8F%

>,&05(,8% /("0C(/% -"#$% (,54:-(/% (K#5(,#48% *"#&(0,8% +"(% *"#1(88(/% &'"#45'% +,%

(,/#1?&01% *+&'=+?% +,/% *"(8(,&(/% #,% &'(% 1(::% 84"-+1(% #-% >H68% #,% .36L772% 4:&0$+&(:?%

&+"5(&0,5% "(1#5,0&0#,% D?% 6)R^m% U% '(:*("% 1(::8F% >:&'#45'% .36L7% +,/% L77% +"(% &"055("0,5%

/08&0,1&% 84D5"#4*8% #-% U% :?$*'#1?&(82% D#&'% $#:(14:(% 1:+88(8% '+C(% 80$0:+"% #C("+::%

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&'+&%1#,808&%#-%+%$($D"+,(%8*+,,0,5%&+0:%-#::#=(/%D?%&=#%(K&"+1(::4:+"%75L:0;(%/#$+0,8%%

% BB%

%

K(570-/ UQ/ V@-0%$$/ +'07,'70-/ )#/ '6-/ 9:3*!/ &)$-,7$-/ %"./ ;-;'(.-*8(".("5/ ,$-#'Q/ ?Q% 6"?8&+:% 8&"41&4"(% #-%

.36L7%WH)J%7)e%B<MIXF%.36L7%'(+C?%1'+0,%0,%5"((,2%w@$%0,%1?+,2%80/(%C0(=%HQ%E:(1&"#8&+&01%"(*"(8(,&+&0#,%

#-%.36L72%/08*:+?0,5%&'(%*(*&0/(%D0,/0,5%1:(-&%+,/%80K%$+]#"%*#1;(&8%W>L!X2%&#*%C0(=F%

W&'(% :+&&("% 0$*#"&+,&% -#"% 6)Q^R% (,5+5($(,&% +,/^#"% "(1#5,0&0#,% D?% 8*(10-01% O9%

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*+"+::(:%D"#;(,%!L'(:01(8%&'+&%+"(%/0+5#,+::?%:#1+&(/%#C("%(05'&%+,&0L*+"+::(:%"L8'((&8%

(8&+D:08'0,5%+%"(8&"01&0C(%8+,/=01'L:0;(%:+,/81+*(%-#"%*(*&0/(%D0,/0,5%+,/%*"(8(,&+&0#,F%

U'(%$+0,%/0--("(,1(8%D(&=((,%&'(%&=#%.36%1:+88(8%"(84:&%-"#$%+:&("+&0#,8%0,%/#$+0,%

#"5+,0[+&0#,8% &'+&% +::#=% D#&'% 1:+88(8% &#% +1'0(C(% /081"(&(% 1'+"+1&("08&018% 0,% &'"((L /0$(,80#,+:%8&"41&4"(8%+,/%&'48%*"(8(,&+&0#,%#-%*(*&0/(%"(*("&#0"(^BAT2BARF%%

.#"(% 8*(10-01+::?2% .36L7% 08% 1#$*"08(/% #-% +% 80,5:(% $($D"+,(% 8*+,,0,5% '(+C?% 1'+0,%

1#$*#8(/%#-%&'"((%xL/#$+0,82%='01'%+:8#%(8&+D:08'(8%&'(%*(*&0/(LD0,/0,5%5"##C(F%U'(%

'(+C?%1'+0,%D0,/8%,#,L1#C+:(,&:?%&#%+%8#:4D:(%75L:0;(%$#:(14:(%1+::(/%"@L$01"#5:#D4:0,%

W"@$X%WK(570-/U?XF%7,%1#,&"+8&2%.36L77%08%1#$*#8(/%#-%&=#%80$0:+":?%80[(/%'(+C?%1'+0,8%

1+::(/%x%+,/%w2%='01'%1#,&"0D4&(%(f4+::?%&#%&'(%*(*&0/(LD0,/0,5%5"##C(F%.36L7%+,/%L77%

*"(8(,&% *(*&0/(8% #-% /0--("0,5% 80[(8% +,/% *"#*("&0(8% +8% +% "(84:&% #-% /0--("(,&0+::?% D40:&%

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.36L7%1+,%+11#$$#/+&(%QLBA%+$0,#%+10/L:#,5%*(*&0/(8%80,1(%&'(%*(*&0/(LD0,/0,5%1:(-&%

08%1:#8(/%+&%D#&'%(,/8^BAT2BARF%6#,C("8(:?2%:#,5("%*(*&0/(8%1+,%D(%*"(8(,&(/%D?%.36L77%

80,1(% &'(% (,/8% #-% &'(% *(*&0/(LD0,/0,5% 1:(-&% +"(% #*(,2% +::#=0,5% :#,5("% *(*&0/(8% &#%

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$#"(%#"%:(88%0,%&'(%$0//:(%/(*(,/0,5%#,%&'(%80[(%+,/%&'(%1'($08&"?%#-%&'(%*"(8(,&(/%

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B@%%

-#"%U6a%81+,,0,5%0,%&'(%1+8(%#-%.36L7L"(8&"01&(/%(*0&#*(8F%>//0&0#,+::?2%:#,5("%*(*&0/(8%

1+,%+:8#%D0,/%&#%.36L7%=0&'%(0&'("%+,%(C(,%$#"(%D4:5(/%8&"41&4"(%#"%D?%(K&(,/0,5%#4&%

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!0,+::?%0&%8'#4:/%D(%,#&(/%&'+&%8(C("+:%C("?%:#,5%C0"+:%*(*&0/(8%+,/%&4$#"L+88#10+&(/%

+,&05(,8% WU>>8X% &'+&% D4:5(% #4&% -"#$% &'(% *(*&0/(LD0,/0,5% 5"##C(2% '+C(% D((,% &'"((L /0$(,80#,+::?%(8&+D:08'(/%+,/%&'#"#45':?%-4,1&0#,+::?%8&4/0(/^BAPLBBTF%

1.5.1 Structural insights into peptide-MHC binding and restriction

.36%$#:(14:(8%$+;(%48(%#-%&'(0"%*(*&0/(LD0,/0,5%80&(8%0,%#"/("%&#%*"(8(,&%+,&05(,8%&#%

U%1(::8F%H+$(:+%J]\";$+,%+,/%)#,%G0:(?%*"#C0/(/%&'(%-0"8&%0,805'&8%0,&#%&'(%8&"41&4"+:%

+,/% D0#1'($01+:% -(+&4"(8% #-% .36^*(*&0/(% "(8&"01&0#,% ='(,% &'(?% /(&("$0,(/% &'(%

1"?8&+:%8&"41&4"(%#-%3b>L>@^BBR2BBSF%<0,1(%&'(,%8(C("+:%8&"41&4"+:%+,/%D0#1'($01+:%8&4/0(8%

'+C(%*"#C0/(/%+,/%8&0::%*"#C0/(%+//0&0#,+:%0$*#"&+,&%0,-#"$+&0#,2%+//0,5%1#,8&+,&:?%&#%

#4"%4,/("8&+,/0,5%#-%&'(%$#:(14:+"%D+808%4,/(":?0,5%.36^*(*&0/(%"(8&"01&0#,F%%

%>:&'#45'%+,%#C("80$*:0-01+&0#,2%0&%08%1#,80/("(/%&'+&%&'(%*(*&0/(LD0,/0,5%1:(-&%#-%.36L7%

1#,808&8%#-%80K%$+]#"%*#1;(&8%&'+&%+11#$$#/+&(%&'(%*"(8(,&(/%*(*&0/(8%SK(570-/ UHTF%

E+1'% #-% &'(8(% *#1;(&82% ,+$(/% >% &#% !2% *:+?8% +,% 0$*#"&+,&% "#:(% 0,% *(*&0/(% D0,/0,5F%

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*(*&0/(LD0,/0,5% 5"##C(8F% U'08% /0"(1&0#,+:% D0,/0,5% 08% +1'0(C(/% &'"#45'% &'(% 4,0f4(%

1'($01+:% (,C0"#,$(,&% 1"(+&(/% D?% 1#,8("C(/% +$0,#% +10/8% 0,% &'(% C010,0&?% #-% &'(8(%

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